In the current age of drug resistance, antimalarial choices are inadequate. In order to support the recent eradication agenda, new generations of both chemoprophylactic and chemotherapeutic antimalarials need to meet the following target product profiles: 1) efficacy against multidrug-resistant malaria; 2) activity against pre- erythrocytic parasites to prevent infection; 3) efficacy against gametocytes for transmission blocking; 4) ability to prevent relapse by targeting the hypnozoite forms of the parasites. We have discovered a novel antimalarial acridone chemotype with broad- spectrum activity against both liver stage and blood stage malaria, with potential to be effective against gametocytes and hypnozoites as well. Our proposed work in this application seeks to develop novel, potent, safe, and inexpensive antimalarial drugs for both prevention and treatment of malaria, thus supporting world-wide elimination of the disease. The specific goal of this project is to conduct lead optimization studies to produce candidates for full preclinical testing that retain the broad-spectrum features and demonstrate enhanced efficacy, safety and pharmacokinetic profiles that warrant further development; to investigate the propensity for drug resistance to selected acridone candidates and identify the molecular target(s) through whole genome sequencing and analysis; and to explore mode of action(s) for these broad-spectrum antimalarial acridones using functional assays and bioanalytical approaches.